Autosomal recessive hypertrophic cardiomyopathy associated with variants in TRIM63

Background Hypertrophic cardiomyopathy (HCM) is typically linked to dominant variants in sarcomeric genes, but rare minor genes, including TRIM63 coding for an E3 ubiquitin-protein ligase, have recently emerged as potential causes of recessive HCM. Methods and results Among 517 adult patients with clinical HCM who underwent next-generation sequencing, we found six index cases carrying biallelic TRIM63 variants—four homozygous and two compound heterozygous. They presented with early-onset disease, marked concentric hypertrophy, diffuse myocardial fibrosis, and progressive left ventricular dysfunction. One patient underwent heart transplantation. No cardiac disease was found in heterozygous relatives. Conclusions TRIM63 -related HCM is rare but clinically distinct. Early identification of TRIM63 homozygous and two compound heterozygous variants in HCM is crucial and warrants proactive clinical surveillance. Take home messages: •TRIM63-related HCM is a rare autosomal-recessive subtype with early onset and severe phenotypes. •Rapid disease progression is common, with extensive fibrosis and frequent transition to hypokinetic-dilated end-stage cardiomyopathy. •Early genetic diagnosis supports proactive management, including timely ICD implantation for arrhythmia risk and reproductive counselling for families due to the recessive inheritance.